Mechanical failure of heart muscle is one of the leading causes of in-hospital deaths in patients with acute myocardial infarction (AMI). Friedberg C. K., 1968, Circulation 39 suppl. IV: 252. An important determinant in the development of such failure is the amount of necrotic tissue in the jeopardized myocardium. Pare D. L. et al., 1971, New Eng J Med 285: 133. Experimental studies in animals have shown that irreversible myocardial cell injury starts about 30 minutes after occlusion of coronary vessels and proceeds for hours. Maroko P. R. et al., 1973, Ann Int Med 79: 720. However, even interventions given as late as 6 hours after cornary occlusion are able to reduce infarction size after AMI by about 35% compared to untreated control animals. Libby P. et al., 1973, J Clin Invest 52: 599. Electro-cardiographic studies indicate that also in humans a substantial amount of myocardial tissue may not become irreversibly injured until hours or even days after occlusion of the coronary vessel, i.e. at a time that most patients will have been admitted to a hospital. Reid P. R. et al., 1974, New Engl J Med 290: 123. A number of experimental and clinical studies have attempted to minimize infarction size by reducing the myocardial necrosis that occurs in the later stages of AMI. Maroko P. R. et al., 1973, Ann Int Med 79: 720.
The later phase of myocardial cell injury likely results from an ensuing acute inflammatory reaction characterized by infiltration of neutrophilic granulocytes (neutrophils). Entman M. L. et al., 1991, FASEB J 5: 2529. Initially, the importance of an inflammatory reaction in mediating myocardial cell injury during AMI was recognized in animal studies which showed that corticosteroids could reduce infarction size by 20 to 35%. Libby P. et al., 1973, J Clin Invest 52: 599;Maclean D. et al., 1978, J Clin Invest 61: 541. However, clinical application of methyl-prednisolone in AMI to minimize myocardial necrosis, was not successful mainly because this treatment interfered with scar formation and healing, leading in some patients to the development of aneurysm and rupture of the ventricle wall. Roberts R. et al., 1976, Circulation 53 Suppl. I: 204. A similar effect has been observed in long-term experiments in rats. Maclean D. et al., 1978, J Clin Invest 61: 541. These disappointing results tuned down further clinical studies that aimed at reducing infarction size by attenuating the inflammatory reaction following AMI.
The inflammatory reaction which occurs in the course of AMI comprises some important events: the local production of chemotactic factors, the infiltration and activation of neutrophils, the local production of cytokines (such as tumor necrosis factor-.alpha. and interleukin-6) to enhance adherence of neutrophils to cardiac myocytes, and the local activation of the complement system. Entman M. L. et al., 1991, FASEB J 5: 2529.
A role of complement activation in AMI was initially suggested by Hill and Ward who provided evidence that complement activation products generated in the infarcted myocardium were responsible for the infiltration of neutrophils. Hill J. H. et al., 1970, J Exp Med 131: 885. Later studies showed that plasma levels of activated complement components are increased in patients with AMI and that several complement components become localized in the infarcted area during the course of AMI, as has been demonstrated both in animals as well as in patients. Pinckard R. N. et al., 1975, J Clin Invest 56: 740; Langlois P. F. et al., 1988, Atherosclerosis 70: 95; Yasuda M. et al., 1990, Circulation 81: 156; Pinckard R. N. et al., 1980, J Clin Invest 66: 1050; McManus L. M. et al., 1983, Lab Invest 48: 436; Schafer H. et al., 1986, J Immunol 137: 1945; Hugo F. et al., 1990, Clin Exp Immunol 81: 132.
Furthermore, a number of studies have demonstrated that complement activation products such as the anaphylatoxins and TCC may have deleterious effects on the myocardium by mechanisms dependent and independent of neutrophils, such as the local production of thromboxane A2 and peptidoleukotrienes LTC4 and LTD4, the release of histamine, plasmalemmal disruption and the activation of neutrophils in the coronary circulation with subsequent plugging of capillary vessels, formation of toxic oxygen radicals and the release of proteolytic enzymes. These mechanisms may lead to vasoconstriction, impaired micro-circulation, an increase in coronary perfusion pressure, and result in ischaemia, contractile failure of the myocardium, tachycardia and impairment of atrioventricular conduction. Del Balzo U. et al., 1984, Proc Natl Acad Sci USA 82: 886; Martin S. E. et al., 1988, Circ Res 63: 483; Ito B. R. et al., 1989, Circ Res 65: 1220; Del Bazzo U. et al., 1989, Circ Res 65: 847; Ito B. R. et al., 1990, Circ Res 66: 596; Stahl G. L. et al., 1990, Circ Res 66: 1103; Engler R. L. et al., 1991, FASEB J 5: 2983; Homeister J. W. et al., 1992, Circ Res 71: 303.
The molecular mechanism of the observed activation of complement during AMI is not clear, although released mitochondrial constituents, presumably membranes, have been frequently claimed to induce the activation. Pinckard R. N. et al., 1973, J Immunol 110: 1376; Pinckard R. N. et al., 1975, J Clin Invest 56: 740; Giclas P. C. et al., 1979, J Immunol 122: 146; Storrs S. B. et al., 1981, J Biol Chem 256: 10924; Rossen R. D. et al., 1988, Circ Res 62: 572; Kagiyama A. et al., 1989, Circ Res 64: 607. However, it should be noted that most of these studies dealt with activation of complement following reperfusion of ischaemic myocardium rather then that following ischaemia due to permanent occlusion of coronary vessels. The deleterious effects of complement activation products on the myocardium have been substantiated by observations that in animal models complement depletion prior to or shortly after permanent occlusion of a coronary vessel significantly reduces the amount of myocardial necrosis. Maroko P. R. et al., 1978, J Clin Invest 61: 661; Maclean D. et al., 1978, J Clin Invest 61: 541; Pinckard R. N. et al., 1980, J Clin Invest 66: 1050; Crawford H. R. et al., 1988, Circulation 78: 1449. None of the studies investigating the effect of complement inhibition on myocardial damage after permanent occlusion of a coronary vessel have used a true inhibitor of the complement cascade, all these studies were done with an agent, i.e. Cobra Venom Factor, that intravascularly activates and depletes the system. However, this method of complement inhibition/depletion cannot be used in clinical situations considering the inherent dangers of intravascular complement activation such as the development of adult respiratory distress. Goldstein IM, 1992, In: Gallin JI, Goldstein IM, Snyderman R (eds): Inflammation: Basic Principles and Clinical Correlates, New York, Raven Press, p.63; Craddock P. R. et al., 1977, New Eng J Med 296: 769; Stimler N. P. et al., 1980, Am J Pathol 100: 327; Hosea S. F. et al., 1980,J Clin Invest 66: 375; Ward P. A. et al., 1985, J Clin Invest 76: 517.
The discussion above deals with activation of the complement system during permanent occlusion of coronary vessels. However, it is now generally accepted to treat patients with AMI with thrombolytic therapy or coronary angioplasty to reperfuse the jeopardized myocardium. The sooner after the occlusion this therapy is given, the more effective it is to salvage the ischaemic myocardium. Clinical studies indicate that more than half of the effect of thrombolytic therapy is lost when treatment is delayed 60-75 minutes. Hermens WTh et al., 1992, Lancet 3: 1297. However, more than 90% of the patients with AMI do not reach the hospital within 75 minutes after the occlusion of a coronary artery and, therefore, will hardly benefit from thrombolytic therapy.
There is ample evidence that reperfusion of ischaemic myocardium itself may induce an inflammatory reaction, also known as ischaemic-reperfusion injury, which is caused by activation of complement and neutrophils and the generation of oxygen radicals. Rossen R. D. et al., 1985, Circ Res 57: 119; Rossen R. D. et al., 1988, Circ Res 62: 572; Dreyer W. J., 1989, Circ Res 65: 1751; Dreyer W. J. et al., 1992, Circ Res 71: 1518; Lucchesi BR et al., 1989, J Mol Cell Cardiol 21: 1271; Engler R et al., 1989, Circulation 79: 1137. This ischaemic-reperfusion injury may damage the cardiac tissue and limit the beneficial effects of a restored circulation. Herdson PB et al., 1965, Am J Pathol 46: 367. Reperfusion therapy in AMI can, therefore, be regarded as a "double edged sword" and is better not applied as late as 2 hours or more after the onset of AMI.
Until now there are no clinical studies in patients with AMI showing activation of complement due to reperfusion of the infarcted myocardium. However, inhibition of complement in these patients may be beneficial since in rats undergoing reperfusion of ischaemic myocardium, treatment with a recombinant soluble form of the human complement receptor type 1 has been shown to reduce myocardial infarction size considerably. Weisman H. F. et al., 1990, Science 249: 146.
To date there is no report in literature describing a beneficial effect of a complement inhibitor (i.e., a protein or substance which inhibits a [activated] complement protein rather then depletes it by activation) on the myocardial infarction size after permanent occlusion of a coronary vessel. The present invention describes a simple method to reduce myocardial infarction size by administering a naturally occurring inhibitor of the activated first component of complement.